Skeletal loading is a powerful osteoanabolic stimulus that has the potential to prevent or reverse the bone loss associated with osteoporosis. Low-amplitude (< 1.0 g), high- frequency (> 20 Hz) loading by whole-body vibration is of particular clinical relevance because it can be delivered as a passive, non-invasive stimulus with few side effects. Initial clinical studies using whole-body vibration have been promising but not uniformly successful in significantly increasing bone density, indicating a need for further investigation. Moreover, the mechanobiological mechanisms by which low-amplitude, high-frequency loading stimulate bone formation are largely unknown. Examination of these mechanisms is complicated in the context of whole-body vibration because it can be difficult to control the local stimulus at the skeletal site of interest. Thus, in order to advance the science of how vibrational loading stimulates bone formation and to complement translational studies using whole-body vibration, there is an unmet need for a model system that enables greater control of the vibrational stimulus to the site of interest. We have designed an apparatus to deliver vertical vibrational loading directly to the lower leg of the mouse, a technique we have termed "constrained tibial vibration". Our overall goal in this R21 developmental project is to characterize the osteogenic response of the murine tibia to constrained tibial vibration. In Aim 1, we will determine the bone formation response of the tibia to vibrational loading under a range of conditions designed to produce different levels of tibial strain. We will determine whether or not the loading response is due to vibration per se or due to bone strain induced by vibrational loading. In Aim 2, we will assess molecular responses by examining solute transport and gene expression induced by constrained tibial vibration. Successful development of the constrained tibial vibration model will establish a basis for future studies in mice with targeted genetic mutations, thus providing a powerful tool for examining the molecular basis of the skeletal response to clinically relevant, low- amplitude, high-frequency loading. [unreadable] [unreadable] [unreadable]